Field of the Invention
The invention relates to the field of chemical synthesis of biologically active compounds on the industrial scale, more particularly to the synthesis of ortho-substituted anilines as intermediates for the subsequent production of fine chemicals and of active ingredients for agriculture, using a flow reactor for continuous performance of the synthesis.
Description of Related Art
The selective exchange of hydrogen in an aromatic system for a substituted carbon atom is one of the fundamental reactions in organic chemistry and is thus known.
The class of compounds which can thus be prepared includes 2-oxindoles (dihydroindol-2-ones) and precursors thereof. Oxindoles and precursors thereof are versatile intermediates for active ingredient syntheses (Bioorg. Med. Chem. Lett. 2006, 16, 2109; JP 2008-101014; WO 96/41799 A1).
Most of the described syntheses of oxindoles, called Stolle syntheses (see scheme 1 (a)), use a variation of the Friedel-Crafts reaction (Stolle Synthesis, W. C. Sumpter, Chem. Rev. 1945, 37, 443-449). However, Stolle syntheses are only of limited utility, since the performance thereof requires strongly acidic conditions and the use of an electron-rich aniline.
Additionally known are free-radical reactions (see scheme 1 (b)), nitrenium ion reactions and organolithium reactions, and also photochemical methods. However, the usability thereof is likewise limited by the type of oxindoles to be prepared in each case, the compatibility of substrates, the reaction conditions, and the condition that the aromatic must already have a substitutable halogen substituent.
Free-radical processes (see scheme 1(b)) are described in: Zard et al., Tetrahedron Lett. 1994, 35, 9553-9556; Zard et al., Tetrahedron Lett. 1994, 35, 1719-1722; Jones et al., Tetrahedron Lett. 1994, 35, 7673-7676; Kikugawa et al., Chem. Letters 1987, 1771-1774; Clark et al., Synthesis 1991, 871-878; Yonemitsu et. al., Chem. Pharm. Bull. 1981, 29, 128-136.

The process of Gassman et al. (Organic Synthesis Coll., Vol. 6, 601 and Vol. 56, 72), which proceeds from aniline and methyl thioacetate ester, via chlorination and treatment with triethylamine at −70° C. (see scheme 2), appears to be suitable with regard to performability, availability of reactants, duration of reaction (reaction rate) and reproducibility.
However, it is known that good yields can be achieved only at low temperatures, namely when the unstable N-chloro (1) or N-sulphonium (2) intermediates which occur during the reaction (see scheme 2) are formed below −65° C., normally at −78° C. (Gassman et. al., J. Am. Chem. Soc., 1974, 96(17), 5508; Gassman et al., J. Am. Chem. Soc., 1974, 96(17), 5512; WO 96/41799 A1). However, the performance of a reaction on the industrial scale at temperatures below −65° C. already entails higher apparatus complexity and is additionally disadvantageous owing to the high operating costs caused by the cooling.

The chlorinating agent of choice, according to the literature, is the unstable and explosive tert-butyl hypochlorite, in which case the by-product of the chlorination gives the neutral tert-butyl alcohol. In the few cases in which sulphuryl chloride (SO2Cl2) has been used as a chlorinating agent, a second, non-nucleophilic base such as “proton sponge” was used (Johnson, J. Org. Chem. 1990, 55, 1374; Warpehoski, Tetrahedron Lett. 1986, 27, 4103). Since both variants have to be performed at low temperatures, however, this is not an advantageous solution for performance of the reaction on the industrial scale. In the Gassman process, the tertiary amine base (C) is not added until the final step (see scheme 2) and serves to deprotonate the intermediate (2) to initiate the conversion of the intermediate (2) to the ortho-substituted aniline (4).
WO 2012/028162 A1 discloses an improved batch process for preparing compounds of the formula (4), likewise proceeding from a thioether and an aniline of the formula (Q), wherein the chlorinating agent used is likewise sulphonyl chloride (SO2Cl2).
The core of the teaching disclosed in WO2012/028162 A1 relates to the finding that an excess of the surprisingly electron-poor anilines functions as a mild base in the formation of product of the formula (4). This is surprising with respect to the standard Gassman reaction, which teaches the final addition of an additional tertiary amine (cf. schemes 2 and 3: C=tertiary amine base, e.g.: triethylamine). The aniline is obviously capable of catalysing the rearrangement to the product of the formula (4) and therefore also of eliminating HCl from a chlorosulphonium intermediate of the formula (3), which would lead only to side reactions. There are no pointers in the document cited to particular measures for performance of the reaction disclosed in WO 2012/028162 A1 using a flow reactor for continuous performance of the synthesis.
U.S. Pat. No. 3,972,894 discloses a further batch process developed by Gassman, in which oxindoles are prepared by first preparing ortho-substituted anilines as intermediates. The reactants used to obtain the ortho-substituted anilines are N-haloanilines and β-thioesters or β-thioamides. The conversion of the reactants likewise forms an azasulphonium compound of the formula (2) as an intermediate, and this is likewise only reacted with a base to give an ortho-substituted aniline in the final step (see scheme 2). Suitable bases mentioned are relatively short-chain alkylamines, such as ethylamine, diethylamine, triethylamine, tributylamine, and aromatic amines, for example pyridine. There are no pointers in the document cited to particular measures for performance of the reaction disclosed in U.S. Pat. No. 3,972,894 using a flow reactor for continuous performance of the synthesis.
For the synthesis of oxindoles, the product (4) obtained by the use of the Gassman reaction is a key precursor. A new alternative for further conversion of compounds (4) to the respective oxindole is described in WO 2010/127786 A1.
A further alternative for preparation of ortho-substituted anilines of the formula (4) is described by Wright et al. (Tetrahedron Lett. 1996, 37, 4631). This involves preparing the chlorosulphonium intermediate (3) from a sulphoxide and oxalyl chloride and further conversion to the product of the formula (4) (see scheme 3). In the process described by Wright et al., the tertiary amine base (C) is not added until the final step (see scheme 3).
However, the chlorosulphonium intermediate (3) is likewise unstable. Moreover, for this reaction, the sulphoxide first has to be prepared and isolated. For reasons of stability, the reaction likewise has to proceed at low temperatures, namely at −78° C. In addition, the reaction has to be conducted stepwise in order to avoid a reaction between aniline and oxalyl chloride.

The reasons for the sensitivity of the reactions shown in scheme 3 to relatively high reaction temperatures, i.e. to reaction temperature exceeding −70° C., and the reasons for the necessity of always performing the reaction stepwise, are various.
It is firstly essential that the functional groups in the reaction shown in scheme 3, i.e. the nitrogen atom of the aniline and the sulphur atom of the thioether, occur unchanged both in the product (4) and in the reactant.
Against this background, a selective chlorination in which the product (4) is formed directly, i.e. during the reaction, and simultaneously with high yield, i.e. quantitatively, would not be expected. This also explains why all methods known from the literature use, or suggest, a stepwise reaction regime.
Moreover, in the chlorination of compounds such as anilines, the problem of ring chlorination arises, i.e. that of unwanted chlorination of the aromatic benzene ring rather than the desired chlorination of the amino substituent. As a result of ring chlorination, the N-chloroaniline can be converted to a ring-chlorinated aromatic at reaction temperatures exceeding −65° C. (see scheme 4).
According to Lengyel et al., the problem of ring chlorination can be illustrated by the example of acetanilide. The probability of ring chlorination depends on whether the benzene ring is electron-rich or rather electron-poor. Even though acetanilide is much less electron-rich compared to N-chloroaniline and should thus have a much lower tendency to ring chlorination, ring chlorination proceeds with tert-butyl hypochlorite as the chlorinating agent even at a reaction temperature of 0° C. (Lengyel et al. Synth. Comm., 1998, 28 (10), 1891-1896).
Furthermore, the sulphonium intermediates (2) or (3) in the presence of bases can form the reactive by-product (5) through elimination. The reactive by-product (5) can condense, for example, with an aniline. In this case, the Pummerer oxidation of the R2—CH—R3 radical irreversibly produced the secondary component (6) (see scheme 4). In addition, other oxidation products (dimers) can also form.

(The designations of the reactants and the other reagents in scheme 4 correspond to the designations from scheme 3.)
WO 2010/127786 A1 describes how some of the aforementioned disadvantages can be overcome, and the executability of an industrial batch reaction is demonstrated by examples. In the case of performance of a batch reaction according to WO 2010/127786 A1, however, temperatures below −20° C. are regarded as necessary, and so the performance of the batch reaction on the industrial scale gives rise to high energy costs. Moreover, the repeated requirement for cooling of the batch vessel proceeding from room temperature to below −20° C. takes a lot of time.
Against this background, it would be a considerable advantage if it were possible to perform the reaction for preparation of compounds of the formula (4) in a flow reactor.
In a flow reactor, a small volume compared to the batch reaction has to be brought to low temperature, and the further reaction can be performed continuously, i.e. without interruption. The advantages of use of a flow reactor consist, in general terms, in the improvement of productivity with a simplified process procedure.
However, the application of the reaction conditions envisaged for the performance of a batch reaction and disclosed in WO 2010/127786 A1 to the conditions in a flow reactor, i.e. the application of the conditions to the continuous performance of the reaction in a flow reactor, was found to be problematic and impracticable due to the formation of sparingly soluble salts in the reaction mixture alone.
In fact, reactions in which salts are formed are very difficult to accomplish in flow reactors if these salts precipitate as solids. Such solids in a flow reactor cause the incrustation and blockage of the microchannels and small-volume mixing chambers. However, the function of a flow reactor system is based specifically on the accessibility of these microchannels and mixing chambers. The precipitates formed during the reaction and the suspensions which arise therefrom should therefore absolutely be avoided if a reaction is to be performable in a flow reactor without interruption and in a reliable manner. Also particularly unfavourable is the occurrence of sparingly soluble salts and/or of viscous suspensions if a reaction is to be executed with a concentration of industrial relevance, i.e. on the industrial scale.
The use of the conditions disclosed in WO 2010/127786 A1, which are directed solely to the performance of the batch process, in the continuous performance of the reaction in a flow reactor was found to be very problematic.
The difficulties could be based on the fact that the aniline used as the reactant in the present process is chlorinated in the presence of a chlorinating agent during the reaction because of its basic properties. The chlorination gives rise to HCl, but at least some of the chlorinated aniline precipitates out as the solid HCl salt in the presence thereof.
In a batch reaction, these precipitates, in contrast to the performance of the same reaction in a flow reactor, are not troublesome to any greater degree, because the HCl salt of the aniline is in equilibrium with the free aniline. This is true even when the equilibrium is established only slowly owing to the solubility of the salt. In a batch reaction, this equilibrium can be re-established again and again with progressive chlorination, and so new aniline is repeatedly available for the reaction in spite of the decreasing amount of free aniline.
In the case of performance of the same reaction in a flow reactor, in contrast, the boundary conditions for the new establishment of the equilibrium do not exist. The main reason for this is the comparatively short residence time of the reactants in the respective reactor section provided for the running of the reaction in the flow reactor. Therefore, the establishment of a chemical equilibrium can proceed only to a very limited degree, if at all, in the respective section of a flow reactor.
In the case of application of the conditions established for the batch reaction to the performance of the same reaction in a flow reactor, the reactant precipitates out as the aniline-HCl salt. This salt formation gives rise to a thick, i.e. highly viscous, suspension. This suspension cannot be conveyed, and so the passage of the reaction mixture through the components which form the flow reactor is either made very difficult or is impossible.
Moreover, the salt formation removes the aniline reactant from the reaction, and so an excess of chlorinating agent arises in the next reaction section of the flow reactor. This excess increases the probability that unwanted side reactions will occur, more particularly the unwanted chlorination of the thioether likewise used as the reactant.